Adiponectin Receptor 1 (ADIPOR1) is a seven transmembrane G protein coupled receptor (GPCR). See, for example, WO 01/012662 and WO 01/090304. Many medically significant biological processes are mediated by signal transduction pathways that involve G-proteins [Lefkowitz, Nature 351, 353-354 (1991)]. Certain extra cellular messengers (ECM) or C-terminal fragments (CTF), which are peptide fragments from the C-terminal of ADIPOR1 (R1 CTF) and ADIPOR2 (R2 CTF), have diagnostic value in human blood. Their usefulness was confirmed using a polyclonal antibody with a mass measuring SELDI-TOF immuno-affinity method. Those inventions are the subject of related application WO 2007/120,311, which is incorporated herein by reference. In that work, a particular long peptide sequence of 32 amino acids of R1 CTF was identified that was completely absent from all diabetic patients tested. Shorter peptide sequences were also found in blood but in both healthy and diabetic patients. The levels of the shorter peptide sequences were generally increased with disease state.
It was also previously discovered that monomeric ECM32 (SEQ ID NO:1) (R1 CTF32), a fragment of 3473 Da as confirmed by two separate monoclonal antibodies, when administered to patients, acted as an insulin-sensitizing agent. That invention is the subject of copending application U.S. Ser. No. 12/169,983 filed Jul. 9, 2008. As such, this C-terminal fragment of ADIPOR1 may be a useful therapeutic agent to increase insulin secretion in patients in need thereof, including, but not limited to, patients suffering from diabetes, abnormal adipocyte activity, and insulin resistance.
It has now been discovered that the dimeric forms of ECM32 and dimeric forms of ECM25 are biologically active. It has also been discovered that heterodimeric form of ECM32, or R1 CTF32 R2 CTF32 (SEQ ID NO:1 linked via a disulfide bond to SEQ ID NO:2), is more active than homodimeric forms of ECM32 (R1 CTF32 R1 CTF32) (SEQ ID NO:1 linked via a disulfide bond to SEQ ID NO:1 or SEQ ID NO:2 linked via a disulfide bond to SEQ ID NO:2)). The methods, compositions, dosage forms, and kits of the present invention are directed toward these, as well as other, important ends.